Immunohistochemistry of aberrant neuronal development induced by 6-propyl-2-thiouracil in rats

• Published in: Toxicology letters Vol. 261; pp. 59 - 71
• Main Authors: Shiraki, Ayako, Tanaka, Takeshi, Watanabe, Yousuke, Saito, Fumiyo, Akahori, Yumi, Imatanaka, Nobuya, Yoshida, Toshinori, Shibutani, Makoto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ireland Ltd 02.11.2016
• Subjects: Animals; Biomarkers; Developmental neurotoxicity; Drinking water; Exposure; Female; GABAergic interneuron; Granular materials; Granules; Hippocampal neurogenesis; Hypothyroidism; Male; Neurogenesis - drug effects; Neurons - drug effects; Parameter identification; Parameter sensitivity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil - toxicity; Rat; Rats; Toxicity; Toxicity study; Toxicity study; PCNA; Rat; PND; SGZ; Hippocampal neurogenesis; DNT; CALB2; PTU; SOX2; RELN; TUNEL; NPY; DPYSL3; COX2; RSGb; GD; CA; T3; EOMES; T4; GABAergic interneuron; EPHA4; RSA; DAB; TSH; PAX6; FOS; Developmental neurotoxicity; Hypothyroidism; GFAP; GCL; ARC; SST; DCX; GABA; VIP; PVALB; THs
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2016.08.019

•DNT parameters were examined in rat PTU-induced hypothyroidism models.•DNT parameters were also examined in an adult-onset hypothyroidism model.•Interneuron changes may be indicative of DNT parameters during development.•Synaptic plasticity and hippocampal neurogenesis are sensitive to PTU-induced DNT.•Hippocampal neurogenesis is sensitive to adult-stage PTU exposure. 6-Propyl-2-thiouracil (PTU)-induced hypothyroidism disrupts neuronal/glial development. This study sought to identify the sensitive immunohistochemical parameters of developmental neurotoxicity (DNT) following PTU-exposure, as well as their responses in a 28-day toxicity study in adults. In the developmental exposure study, pregnant rats were treated with 0, 1, 3, and 10ppm PTU in drinking water from gestational day 6 to postnatal day (PND) 21 and pups were examined on PNDs 21 and 77. In the adult-stage exposure study, 5-week-old male rats were treated with 0, 0.1 and 10mg PTU/kg by oral gavage for 28 days. In the developmental exposure study on PND 21, there were fewer GFAP+, PAX6+, and DCX+ cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus at ≥3 or 10ppm. Regarding synaptic plasticity-related molecules, there were fewer EPHA4+ and ARC+ cells in the dentate granule cell layer. Regarding GABAergic interneuron subpopulations, there were more RELN+, CALB2+, and SST+ cells and fewer PVALB+ cells in the dentate hilus. There were also differences in the numbers of RELN+, PVALB+, CALB2+, and NPY+ cells in the cerebral cortex, and RELN+, PVALB+, and SST+ cells in the cerebellar cortex. Most of these changes were sustained until PND 77. Following adult-stage exposure (10mg/kg), there were fewer SGZ DCX+ cells, but more RELN+ and SST+ cells in the dentate hilus. Results suggest that GABAergic interneuron populations in cortical tissues, hippocampal neurogenesis, and synaptic plasticity are sensitive to PTU-induced DNT during development. In contrast, only hippocampal neurogenesis was sensitive to adult-stage exposure.